Evaluation of Acyclovir for Preemptive Treatment in Mechanically Ventilated ICU Patients with Herpes Simplex Virus Oropharyngeal Reactivation and Limited Organ Failure

The primary objective of this study is to evaluate whether treatment with **acyclovir** reduces mortality at day 60 in mechanically-ventilated patients hospitalized in the ICU with Herpes simplex virus (HSV) throat reactivation and one or fewer organ failures, compared to a placebo. This is clinically relevant as it addresses the potential impact of acyclovir on survival outcomes in a critical care setting, where HSV reactivation can complicate patient management and prognosis.

Secondary objectives include assessing the efficacy of acyclovir compared to placebo on various clinical parameters: - Duration of mechanical ventilation - ICU and hospital length of stay - Kinetics of organ failures from randomization to day 14 - Incidence of herpetic oral-labial lesions - Duration of HSV oropharyngeal shedding - Incidence of HSV colonization of the lower respiratory tract after randomization - Incidence of HSV bronchopneumonitis - Incidence of acute respiratory distress syndrome - Incidence of nosocomial infections, including pneumonia and bloodstream infections

Additionally, the study aims to demonstrate the safety of acyclovir compared to placebo concerning neurological toxicity, renal toxicity (including creatinine clearance and the need for renal replacement therapy), and the frequency and intensity of adverse and severe adverse events. These secondary objectives are crucial for understanding the broader clinical implications of acyclovir use in this patient population, including its potential benefits and risks.

The clinical trial involves a **study population** of patients aged 18 years and older who are hospitalized in the ICU and require invasive mechanical ventilation. Both male and female participants are included, and the trial specifically targets a **vulnerable population**. Participants must have experienced HSV throat reactivation and have one or no organ failures, as defined by a corresponding-organ SOFA score of 3 or 4. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Selection criteria include a requirement for invasive mechanical ventilation for at least 96 hours, with an expectation to continue for at least 48 more hours, and a positive qualitative PCR for HSV on a throat swab. Participants must also be under social security cover and provide written consent, either personally or through a designated representative. Lifestyle factors such as diet and physical activity are not specified in the trial data.

The clinical trial is designed to evaluate the efficacy of **aciclovir** in reducing mortality in patients with **Herpes simplex virus** (HSV) oropharyngeal reactivation who are intubated and mechanically ventilated in the intensive care unit (ICU) with one or less organ failure. This is a randomized, double-blind, placebo-controlled trial. The trial is expected to commence on January 8, 2024, and conclude by March 8, 2027. Participants will be randomly assigned to receive either aciclovir or a placebo, with the primary endpoint being mortality at day 60 post-randomization.

The study will include several key visits: an initial screening visit, multiple follow-up visits, and an end-of-study visit. During the screening visit, eligibility will be confirmed based on criteria such as age (≥18 years), invasive mechanical ventilation for at least 96 hours, and HSV reactivation in the throat. Follow-up visits will occur at specified intervals to monitor various secondary endpoints, including day-90 mortality, duration of mechanical ventilation, and incidence of HSV-related complications. The end-of-study visit will assess the overall outcomes and any adverse events experienced by the participants.

Participants are expected to be involved in the study for a maximum of 14 days of treatment, with follow-up assessments extending to 60 days post-randomization. Conditions that may lead to early termination from the study include withdrawal of consent, significant protocol deviations, or the occurrence of severe adverse events. The trial aims to provide valuable insights into the potential benefits of aciclovir in this patient population, with a focus on improving survival rates and reducing the burden of HSV-related complications in critically ill patients.

The clinical trial involves the administration of **ACICLOVIR**, marketed as ACICLOVIR VIATRIS 500 mg, which is provided in the form of a **POWDER FOR SOLUTION FOR INJECTION**. This medication is intended for **INTRAVENOUS USE**. The maximum daily dose is 1500 mg, with a total maximum dose of 21000 mg over a treatment period of up to 14 days. The active substance, aciclovir, is of chemical origin and is utilized to assess its efficacy in reducing mortality in mechanically-ventilated patients with **Herpes simplex virus** throat reactivation and one or less organ failure. The product is manufactured by VIATRIS SANTE and holds the marketing authorization number NL 23490.

In addition to the experimental treatment, the trial employs **SODIUM CHLORIDE** 0.9% B. BRAUN, a **SOLUTION FOR INJECTION** provided in ampoules. This solution is used as a placebo and is administered via **INTRAVENOUS INFUSION**. The maximum daily volume is 20 ml, with a total maximum volume of 840 ml over a 14-day period. The sodium chloride solution is of chemical origin and is produced by B.BRAUN MELSUNGEN AG, with the marketing authorization number 34009 218 974 0 1. This placebo is used to compare the effects of aciclovir treatment against a standard non-active treatment in the study population.

Efficacy in this clinical trial will be assessed primarily by evaluating the reduction in mortality at day 60 post-randomization in mechanically ventilated patients with **Herpes simplex virus** (HSV) throat reactivation and one or less organ failure, treated with acyclovir compared to a placebo. Secondary endpoints include day-90 mortality, duration of mechanical ventilation, ventilator-free days at day 60, ICU and hospital length of stay, and ICU-free and hospital-free days at day 60. Additional secondary endpoints involve the Sequential Organ Failure Assessment (SOFA) score at multiple timepoints (days 1, 3, 5, 7, 10, 14, 21, and 28 post-randomization), incidence of HSV oral-labial lesions, and rates of HSV positivity in the throat and tracheal aspirate at specified intervals.

Further secondary endpoints include the rate of HSV bronchopneumonitis, acute respiratory distress syndrome, bacterial ventilator-associated pneumonia, and bacteremia from randomization to day 60. The Glasgow Coma Score will be assessed at days 1, 3, 5, 7, 10, and 14 post-randomization. Creatinine clearance will be measured at days 1, 3, 5, 7, 10, 14, 21, and 28, along with the need for renal replacement therapy and RRT-free days from randomization to day 14, to monitor for acyclovir toxicity. The incidence of adverse and severe adverse events will also be recorded at specified intervals throughout the trial.